Early COVID‐19 XBB.1.5 Vaccine Effectiveness Against Hospitalisation Among Adults Targeted for Vaccination, VEBIS Hospital Network, Europe, October 2023–January 2024

ABSTRACT We conducted a multicentre test‐negative case–control study covering the period from October 2023 to January 2024 among adult patients aged ≥ 18 years hospitalised with severe acute respiratory infection in Europe. We provide early estimates of the effectiveness of the newly adapted XBB.1.5 COVID‐19 vaccines against PCR‐confirmed SARS‐CoV‐2 hospitalisation. Vaccine effectiveness was 49% overall, ranging between 69% at 14–29 days and 40% at 60–105 days post vaccination. The adapted XBB.1.5 COVID‐19 vaccines conferred protection against COVID‐19 hospitalisation in the first 3.5 months post vaccination, with VE > 70% in older adults (≥ 65 years) up to 1 month post vaccination.


| VEBIS Hospital Network
The Vaccine Effectiveness, Burden and Impact Studies (VEBIS) hospital study is a multicentre, test-negative, casecontrol study.The VEBIS hospital network includes 65 hospitals in 11 participating EU/EEA countries (Figure 1), following a common generic protocol [4].We included patients with severe acute respiratory infection (SARI), defined as those hospitalised for ≥ 24 h, with at least one of the following symptoms: fever, cough, shortness of breath or sudden onset of anosmia, ageusia or dysgeusia [5], adapted for local use.We defined cases as SARI patients testing positive for SARS-CoV-2 by PCR within 48 h of admission or, if known, in the previous 14 days and controls as PCR-negative within 48 h, with no positive test in the previous 14 days (if known).We excluded SARI patients with missing or erroneous information on key variables (sex, age, chronic conditions and dates of onset, swab and hospital admission), as well as sites with fewer than five cases or controls or with no vaccinated patients in both case and control groups (Figure S1).We restricted the analysis to adults ≥ 18 years, targeted by the vaccine recommendations in each study site (older adults aged ≥ 50, ≥ 55, ≥ 60 or ≥ 65 years old and those in medical risk groups, as defined locally; Table S2).The study period began 14 days after the start of the 2023 autumn vaccination campaign, varying by study site (Table S1).Overall, the study period was from 05 October 2023 to 14 January 2024.

| Vaccination Definition and SARI Patient Description
We defined SARI patients as vaccinated if they received their most recent COVID-19 vaccine dose after the start of the 2023 autumn vaccination campaign in their study site, regardless of their previous vaccination history, and at least 14 days before symptom onset.Where known, we excluded patients with a vaccine other than XBB.1.5 or with vaccine brand other than Comirnaty, Spikevax or Nuvaxovid (information not collected by all sites).We defined unvaccinated SARI patients as those who had never received a COVID-19 vaccine or with last dose received at least 180 days prior to the start of the 2023 autumn vaccination campaign in each study site.We excluded those vaccinated 1-13 days before symptom onset.
We included 622 SARS-CoV-2 cases and 3457 test-negative controls aged ≥ 18 years from 41 hospitals in seven sites, after exclusions (one site was excluded for data quality issues, one had fewer than five cases and three had no vaccinated patients in both case and control groups; Figure S1).

| Vaccine Effectiveness
We estimated the odds ratio (OR) of vaccination between cases and controls using logistic regression with study site as a fixed effect and adjusted for date of symptom onset, sex, age and presence of a chronic condition.The VE was calculated as (1 − OR) × 100%.We estimated VE overall and by time since vaccination (TSV) in 30-day bands, for all adults and by age group (18-59, 60-79, ≥ 80 and ≥ 65 years).Estimates were not shown if there were < 20 vaccinated patients; fewer than five vaccinated/unvaccinated cases or controls; or when the OR estimate had an absolute difference > 10% from the OR estimated using penalised logistic regression (to assess small sample bias).
We conducted the following sensitivity analyses: (1) inclusion of SARI patients with symptom onset at least 7 days (instead of 14 days) after vaccination; (2) VE for those with symptom onset in the period 7-13 days post vaccination.
Sensitivity analyses including patients with symptom onset from 7-29 instead of 14-29 days post vaccination showed mostly  S2).
b Only among patients that have received at least one COVID-19 vaccine dose.The interquartile range (IQR) is presented as the first (25% percentile) and third (75% percentile) quartile of the time since vaccination among patients that have received at least one COVID-19 vaccine dose.c The odds ratio (OR) of vaccination is estimated using logistic regression model with fixed effects, adjusted for site, date of symptom onset, sex, age and presence of any chronic condition (diabetes, heart disease, lung disease, asthma and immunodeficiency).The best functional forms of the continuous variables age and onset date (categories, splines, linear terms) were selected using the Akaike information criterion.Vaccine effectiveness is given by VE = (1 − OR) × 100%.d All individuals: all those in the target group for vaccination in their study site and aged at least 18 years old.e Unvaccinated: SARI patients who did not receive a vaccine during the 2023 autumn vaccination campaign and were either never vaccinated for COVID-19 or received their last COVID-19 vaccination dose at least 180 days prior to the start of the 2023 autumn vaccination campaign in their study site.f Vaccinated: SARI patients who received a COVID-19 vaccine dose after the start of the 2023 autumn vaccination campaign in their study site, at least 14 days before symptom onset.Patients vaccinated 1-13 days before symptom onset were excluded.We excluded patients with a vaccine other than XBB.1.5 or vaccine brand other than Comirnaty, Spikevax or Nuvaxovid, for the patients with known brand and/or type of the most recent vaccine dose.g Maximum age included in the analysis: 105 years.
lower VE, with absolute differences ranging between 0% and 13%.The VE for those with onset 7-13 days after vaccination ranged between 20% and 28% across groups, albeit with very low precision.

| Discussion
We estimated VE of 49% against SARS-CoV-2 hospitalisation for the adapted XBB.1.5vaccine in the period 05 October 2023-14 January 2024 in Europe.Results by age group showed slightly higher VE point estimates for those aged ≥ 80 years compared to those aged 60-79 years, with overlapping confidence intervals for all estimates.VE declined with TSV, from 69% in the first 29 days to 40% at 60-105 days.
Decline in VE over time has been reported in the literature for other COVID-19 vaccines [6][7][8].The decline might be explained by waning immunity or the SARS-CoV-2 variants in circulation.During our study period, XBB lineages (mostly XBB.1.5-like+F456L)dominated in EU/EEA countries until 18 December 2023, when the BA.2.86 variant became predominant [3].A small number of samples from cases included in the study was sequenced from one study site (35; 5.6%).Of these, 80% were identified as XBB and 20% as BA.2.86.
A study using the screening method in the Netherlands estimated VE against hospitalisation among ≥ 60 years between October and December 2023 to be 70.7%[9].A cohort study in Denmark, during October 2023, found vaccination to be associated with a 76% reduced risk of COVID-19 hospitalisation [10].A preprint of a test-negative study in United States among ≥ 18 years, between 11 October and 10 December 2023, estimated a similar VE against hospital admission to be 63% [11].Our results are slightly lower, possibly explained by our longer median TSV.The US VISION network reported VE among patients aged ≥ 18 years to be 53% in the first 7-59 days post vaccination and 50% at 60-119 days [12].Among patients aged ≥ 65 years, VE was 54% in the first 7-59 days and 50% at 60-119 days.The IVY network estimated VE of 43% among adults aged ≥ 18 years and 48% among adults aged ≥ 65 years.Our results are consistent with these, albeit with a greater decline in VE with increasing TSV, which might be explained by the different choice of TSV bands.Three of these studies included patients as early as 7 days post vaccination [9,10,12], whereas our vaccination eligibility cut-off was at least 14 days.
Our study had some limitations.Although cases are required to meet the SARI case definition and to have a positive SARS-CoV-2 PCR result, they might have been hospitalised for reasons other than COVID-19, which might underestimate our VE [13].In addition, we assumed that vaccines received during the 2023 autumn vaccination campaign were all adapted XBB.1.5COVID-19 vaccines.We excluded non-XBB.

TABLE 2 |
Vaccine effectiveness of the adapted COVID-19 XBB.1.5vaccines against hospitalisation, overall and by time since vaccination, for individuals ≥ 18 years old in the target group for vaccination a and by age group, VEBIS hospital network, Europe, 05 October 2023-14 January 2024 (n = 4079).
Abbreviations: CI: confidence interval; IQR: interquartile range; SARI: severe acute respiratory infection; VEBIS: Vaccine Effectiveness, Burden and Impact Studies.a Groups targeted for the 2023 autumn COVID-19 vaccination include older adults (aged ≥ 50, ≥ 55, ≥ 60 or ≥ 65 years old) and those in medical risk groups, as defined locally by each study site (Table -19 doses received, we could not exclude vaccinated patients who had received a previous COVID-19 vaccine within 180 days prior to the start of the vaccination campaign (as was done for the unvaccinated).Finally, a small sample size for those aged 18-59 years resulted in low precision, and VE by TSV could not be estimated for this group.Our multicentre study also had many strengths.We were able to include data from several countries and sites, allowing us a larger sample size and increased representativeness of the European population, for a pooled VE estimate that might be more generalisable.In addition, sites participating in the network follow a generic protocol, which helps to mitigate potential sources of heterogeneity, and increase internal validity of VE estimates.The findings of our study suggest that the adapted COVID-19 XBB.1.5vaccinesprovided protection against hospitalisation in the first 3.5 months post vaccination, by reducing the risk of COVID-19 hospitalisation by approximately half among the vaccinated individuals.writing-review and editing, data curation, resources.Lenka Součková: investigation, methodology, writing -review and editing, data curation, resources.Alexandru Marin: investigation, methodology, writing -review and editing, data curation, resources.Kristin Tolksdorf: investigation, methodology, writing -review and editing, data curation, resources, supervision.Nathalie Nicolay: conceptualization, project administration, writing -review and editing, validation.Angela M. C. Rose: conceptualization, funding acquisition, supervision, project administration, methodology, writing -review and editing, validation.on behalf of the European Hospital Vaccine Effectiveness Group: conceptualization, methodology, data curation, resources, writing -review and editing, investigation.